<i>Pseudomonas </i>exotoxin A with less immunogenic T cell and/or B cell epitopes

摘要

The invention provides a Pseudomonas exotoxin A (PE) comprising an amino acid sequence having a substitution of one or more B-cell and/or T-cell epitopes. The invention further provides related chimeric molecules, as well as related nucleic acids, recombinant expression vectors, host cells, populations of cells, and pharmaceutical compositions. Methods of treating or preventing cancer in a mammal, methods of inhibiting the growth of a target cell, methods of producing the PE, and methods of producing the chimeric molecule are further provided by the invention.

主权项

1. A Pseudomonas exotoxin A (PE) comprising an amino acid sequence having a substitution of one or more amino acid residues selected from the group consisting of the amino acid residues at positions 421, 422, 423, 425, 427, 429, 439, 440, 443, 444, 446, 447, 450, 463-479, 481-514, 516-519, 551, 552, 554, 555, 556, and 558 of SEQ ID NO: 1; with the proviso that
when the amino acid residue at position 485 or 516 is substituted with alanine, at least one additional amino acid residue at positions 421, 422, 423, 425, 427, 429, 439, 440, 443, 444, 446, 447, 450, 463-479, 481-514, 516-519, 551, 552, 554, 555, 556, and 558 of SEQ ID NO: 1 is substituted, and when the amino acid residue at position 427, 467, 490, 505, 513, or 551 is substituted with alanine, glycine, serine, or glutamine, or when the amino acid residue at position 490 is substituted with valine, leucine, or isoleucine, at least one additional amino acid residue at positions 421, 422, 423, 425, 427, 429, 439, 440, 443, 444, 446, 447, 450, 463-479, 481-514, 516-519, 551, 552, 554, 555, 556, and 558 of SEQ ID NO: 1 is substituted, which does not include a substitution of alanine, glycine, serine, or glutamine for the amino acid residue at position 427, 467, 490, 505, 513, or 551, or a substitution of valine, leucine, or isoleucine for the amino acid residue at position 490, wherein the amino acid residues at positions 421, 422, 423, 425, 427, 429, 439, 440, 443, 444, 446, 447, 450, 463-479, 481-514, 516-519, 551, 552, 554, 555, 556, and 558 are defined by reference to SEQ ID NO: 1, and wherein the PE optionally has a further substitution of one or more amino acid residues within one or more B-cell epitopes of SEQ ID NO: 1.